Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure

Abstract

SummaryThe clinical benefit of endothelin receptor antagonists (ERA) for the management of heart failure (HF) remains controversial. To examine this question, we performed a meta-analysis of randomized controlled trials (RCTs) to investigate the clinical and hemodynamic effects of ERA in HF patients.We searched the PubMed, Medline, Embase, and Cochrane Library from inception to March 20, 2016 to identify the pertinent studies. Risk ratio (RR) and weighted mean difference (WMD) were calculated using a fixed or random effect model.A total of 15 RCTs with 3,624 HF patients were included. Compared with control groups, ERA might not improve the mortality (RR 1.12, 95%CI 0.81 to 1.54, P = 0.51) or incidence of worsening HF or cardiovascular events (WHF/ CVE) (RR 1.06, 95%CI 0.94 to 1.19, P = 0.35) in HF patients. Subgroup analysis also suggested that neither nonselective nor selective ERAs had an impact on mortality and WHF/CVE. However, the hemodynamic variables of HF patients, including cardiac index (WMD 0.32, 95%CI 0.22 to 0.43, P < 0.01), pulmonary capillary wedge pressure (WMD -3.10, 95%CI -3.99 to -2.20, P < 0.01), mean pulmonary arterial pressure (WMD -4.42, 95%CI -5.50 to -3.33, P < 0.01), systemic vascular resistance (WMD -276.35, 95%CI -399.62 to -153.09, P < 0.01), and pulmonary vascular resistance (WMD -69.42, 95%CI -105.33 to -33.52, P < 0.01) were significantly improved by ERA.In conclusion, this meta-analysis suggests that ERA therapy could effectively improve cardiac output and pulmonary and systemic hemodynamics, but with less benefit to the clinical outcomes of HF patients. (Int Heart J 2017; 58: 400-408) Key words: Endothelin system, Systematic review H eart failure (HF) is a major public health problem, with a prevalence of more than 23 million worldwide. 1) Progression of HF is characterized by sustained deterioration in symptoms, cardiac function, and peripheral and pulmonary vascular resistance.2,3) Neurohormonal activation, an important factor of left ventricular (LV) remodeling, is likely to be a primary determinant for the progression. The roles of activation of the renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in HF are well documented and inhibiting them with angiotensin-converting enzyme inhibitors (ACEI) and β blockers could effectively reverse the process of LV remodeling, relieve patient symptoms, and prolong life. [4][5][6] Furthermore, it has been demonstrated that local activation of the endothelin (ET) system might also be linked with HF progression. 7)ET-1 is thought to mediate potent vasoconstriction, proliferation of vascular smooth muscle, and myocardial hypertrophy through ET A receptors. 8) In contrast, activation of endothelial ET B receptors is primarily involved in vasodilation, antithrombotic, and antiproliferative effects. Moreover, ET-1 also has a potential to enhance the activity of RAS and SNS pathways and induce the production of other neurohormonal factors.9) Plasma levels of ET-1 and big ET-1 are elevated and can significantly predict mortalit...

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

“…This finding thus supports previous concerns about PH-targeted therapies in HFpEF/HFrEF patients, including PDE5-inhibitors[ 47 ]. Conversely, a recent meta-analysis on PDE5-inhibitors in HFrEF/HFpEF observed a reduction of the composite of death or hospitalisation [ 48 , 49 ], whereas another meta-analysis could not find significant changes in mortality with endothelin receptor antagonists[ 50 ]. However, these meta-analyses mainly included trials of short duration.…”

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

“…When 32 studies with 18497 HF patients were summarized in the meta-analysis, it was shown that plasma ET-1 and its related peptides were associated with poor prognosis and mortality in diverse spectrum of HF populations[ 272 ]. On the other hand, a meta-analysis of randomized clinical trials showed that neurohumoral antagonism of ET receptors in HF patients improved cardiac output, pulmonary and systemic hemodynamics but had a modest effect on clinical outcomes[ 273 ]. Therefore, these data suggest that there is a significant discrepancy between these observations – on one hand, ET signaling has been consistently associated with poor outcomes and prognosis in HF and on the other hand, pharmacological targeting of these adverse pathways seems less impressive in improving outcomes.…”

Effect of Palliative Care for Patients with Heart Failure

“…[1][2][3][4] Patients with advanced heart failure experience showed marked reductions in health-related quality of life with common fatigue, dyspnea, and swelling of arms and legs. 1,[5][6][7] In addition, these patients feel uncertain, feared, isolated, and lonely. 8,9) They regarded themselves as a burden to their carers because of assistance requirement in daily living.…”